Journal of Virology, July 2001, p. 6070-6085, Vol. 75, No. 13
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.13.6070-6085.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
andDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30323,1 and Special Pathogens Branch2 and Division of AIDS, STD, and TB Laboratory Research,3 National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
Received 12 December 2000/Accepted 28 March 2001
Sin Nombre virus (SNV) and Hantaan virus (HTN) infect endothelial
cells and are associated with different patterns of increased vascular
permeability during human disease. It is thought that such patterns of
increased vascular permeability are a consequence of endothelial
activation and subsequent dysfunction mediated by differential immune
responses to hantavirus infection. In this study, the ability of
hantavirus to directly induce activation of human lung microvascular
endothelial cells (HMVEC-Ls) was examined. No virus-specific modulation
in the constitutive or cytokine-induced expression of cellular adhesion
molecules (CD40, CD54, CD61, CD62E, CD62P, CD106, and major
histocompatibility complex classes I and II) or in cytokines and
chemokines (eotaxin, tumor necrosis factor alpha, interleukin 1
[IL-1
], IL-6, IL-8, MCP-1, MIP-1
, and MIP-1
) was detected at
either the protein or message level in hantavirus-infected HMVEC-Ls.
Furthermore, no virus-specific enhancement of paracellular or
transcellular permeability or changes in the organization and
distribution of endothelial intercellular junctional proteins was
observed. However, infection with either HTN or SNV resulted in
detectable levels of the chemokines RANTES and IP-10 (the 10-kDa
interferon-inducible protein) in HMVEC-Ls within 72 h and
was associated with nuclear translocation of interferon regulatory
factor 3 (IRF-3) and IRF-7. Gamma interferon (IFN-
)-induced expression of RANTES and IP-10 could also be detected in uninfected HMVEC-Ls and was associated with nuclear translocation of IRF-1 and
IRF-3. Treatment of hantavirus-infected HMVEC-Ls with IFN-
for
24 h resulted in a synergistic enhancement in the expression of
both RANTES and IP-10 and was associated with nuclear translocation of
IRF-1, IRF-3, IRF-7, and NF-
B p65. These results reveal a possible
mechanism by which hantavirus infection and a TH1 immune response can
cooperate to synergistically enhance chemokine expression by HMVEC-Ls
and trigger immune-mediated increases in vascular permeability.
Present address: Department of Pathology, University of Texas
Medical Branch, Galveston, TX 77555.
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